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Small Molecule Therapeutic Designed from Only an RNA Sequence

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Scientists from the Florida campus of The Scripps Research Institute (TSRI) reportedly have developed a potentially general approach to design drugs from a genome sequence. As a proof of principle, they identified a highly potent compound that causes cancer cells to attack themselves and die.

“This is the first time therapeutic small molecules have been rationally designed from only an RNA sequence—something many doubted could be done,” said Matthew Disney, Ph.D., an associate professor at TSRI who led the study. “In this case, we have shown that that approach allows for specific and unprecedented targeting of an RNA that causes cancer.”

The technique, described in Nature Chemical Biology online ahead of print, was dubbed Inforna. “With our program, we can identify compounds with high specificity,” said Sai Pradeep Velagapudi, the first author of the study and a graduate student working in the Disney lab. “In the future, we hope we can design drug candidates for other cancers or for any pathological RNA.”

In their research program, Dr. Disney and his team has been developing approaches to understand the binding of drugs to RNA folds. In particular, the lab is interested in manipulating microRNAs.

Some microRNAs have been associated with diseases. MiR-96 microRNA, for example, is thought to promote cancer by discouraging a process called apoptosis or programmed cell death that can rid the body of cells that begin to grow out of control. As part of its long-term program, the Disney lab developed computational approaches that can mine information against such genome sequences and all cellular RNAs with the goal of identifying drugs that target such disease-associated RNAs while leaving others unaffected.

“In recent years we've seen an explosion of information about the many roles of RNA in biology and medicine,” said Peter Preusch, Ph.D., of the NIH, which partially funded the research. “This new work is another example of how Dr. Disney is pioneering the use of small molecules to manipulate disease-causing RNAs, which have been underexplored as potential drug targets.”

In the new study, Disney and colleagues describe their computational technique, which identifies optimal drug targets by mining a database of drug-RNA sequence (“motif”) interactions against thousands of cellular RNA sequences.

“Inforna was applied to all human microRNA hairpin precursors, and it identified bioactive small molecules that inhibit biogenesis by binding nuclease-processing sites (44% hit rate),” wrote the investigators in their journal article (“Sequence-based design of bioactive small molecules that target precursor microRNAs”). “Among 27 lead interactions, the most avid interaction is between a benzimidazole and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Markedly, microRNA profiling shows that 1 only affects microRNA-96 biogenesis and is at least as selective as an oligonucleotide.”

“This illustrates an unparalleled selectivity for the compound,” noted Dr. Disney. “In contrast, typical cancer therapeutics target cells indiscriminately, often leading to side effects that can make these drugs difficult for patients to tolerate.”

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